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Medulloblastoma in childhood
- revisiting intrathecal therapy in infants and children


Sharon Conroy, Lecturer in Paediatric Clinical Pharmacy
Martin Garnett, Associate Professor Pharmaceutical Sciences
Michael Vloeberghs, Professor Paediatric Neurosurgery
Richard Grundy, Professor Paediatric Neuro-Oncology and Cancer Cell Biology
Ian Craven, Research student
David Walker, Professor Paediatric Oncology


Children's Brain Tumour Research Centre,
University of Nottingham,
University Park,
Nottingham
NG7 2RD
UK

Corresponding author: Professor David A Walker
david.walker@nottingham.ac.uk
Tel: +44 1158 230632.

The authors can confirm that this work is original. It was presented as a poster at the 11
th

International Symposium on Pediatric Neuro-Oncology and the abstract published as below:

Conroy S, Craven I, Garnett M, Barrett S, Punt J, Parker T, Walker DA. An extensive review of
chemotherapy agents suitable for intrathecal (IT) therapy in primitive neuro ectodermal
tumour (PNET). Abstract EXP 7 from 11
th
International Symposium on Pediatric Neuro-
Oncology. Neuro-Oncology 2004;6:428


There are no conflicts of interest to declare. This work was conducted without any financial
assistance outside of the University of Nottingham


The manuscript has been read and approved by all the authors. Each author believes that the
manuscript represents honest work.
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Medulloblastoma in childhood
- revisiting intrathecal therapy in infants and children

Sharon Conroy, Martin Garnett, Michael Vloeberghs, Richard Grundy, Ian Craven
and David Walker


Abstract


Introduction: Intrathecal chemotherapy is being explored in medulloblastoma in pre-school
children as part of brain-sparing strategies and as an alternative to unacceptably neurotoxic
cranio-spinal radiotherapy. The range of drugs suitable for this route of administration is
restricted by the lack of research evidence of pharmacological suitability and efficacy of other
drugs in medulloblastoma.

Methods: Ideal clinical, biological, physicochemical and pharmaceutical properties for
intrathecal administration were defined through literature review of pharmaceutical texts,
Medline, Embase and consulting the manufacturers. 126 chemotherapy agents were assessed
against these criteria by searching the academic domain of pharmaceutical texts, computer
databases and consultation with manufacturers.

Results: Of 126 candidates drugs, 99 were rejected because of documentation of their
irritant nature, neurotoxicity and requirement for hepatic activation in standard pharmaceutical
texts. Fifty were rejected for a single identifiable reason including, neurotoxicity (n=24),
irritant (n=15), needs enzyme activation (n=5), clinical evidence of intrathecal neurotoxicity
(n=4) and no evidence of tumour-specific efficacy (n=2). Where two reasons were cited the
justifications were: neurotoxic and irritant (n=3) and needs activation and systemic
administration results in equivalent concentration (n=1). Twenty seven drugs remained of
which 12 were selected as eligible for further clinical investigation, and 15 were selected for
further pre-clinical investigation.

Conclusions: The predetermined criteria were not applicable, in their entirety, in the majority
of drugs, due to lack of information in the academic domain, emphasising the importance of a
more open approach to sharing basic drug information. The prioritised list of 12 candidate
drugs for clinical trial and 15 for pre-clinical investigation justify that a concerted research
effort in this area of practice is made. (317 words)
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Introduction
Medulloblastoma, the commonest malignant CNS tumour of childhood [125], has the capacity
to disseminate through the lepto-meninges, presenting at diagnosis or at relapse after
treatment. Leptomeningeal metastases (LM) grow at the interface of the brain and spinal
fluid. They are thought to occur as a result of interplay between operative disruption of
tumour cells contaminating the CSF and inherent biological capacity for tumour cells to
migrate, adhere and invade neural tissue. Where LM are present at diagnosis biological factors
are increasingly being associated with this dissemination and poorer cure rates with standard
therapy. Systemic chemotherapy has an established role in medulloblastoma with evidence of
chemosensitivity, enhanced survival rates and rising survival rates reported by trials groups
and population registries [80] in recent eras.

The use of intrathecal chemotherapy in childhood leukaemia and CNS tumours has been the
focus of reviews [17, 49, 108] and reports of phase 1 and 2 studies [17]. In leukaemia the
intensification of systemic and intrathecal therapy has permitted exclusion of CNS radiotherapy
for the majority of newly diagnosed cases with very low CNS relapse rates, acceptable late
toxicity using methotrexate alone or in combination with cytosine and hydrocortisone. The
intrathecal route in leukaemia has been demonstrated to bypass the blood brain barrier (BBB),
enhance CSF drug concentrations reducing systemic exposure and, therefore, toxicity.
Selection of drugs suitable for intrathecal administration and with evidence of sensitivity to
primary CNS tumours is a challenge in medulloblastoma, therefore. Preliminary evidence of
the efficacy of intrathecal therapy is emerging. Slavc reported extensive use of intrathecal
therapy at relapse using etoposide, mafosfamide and others [120, 121]. Other studies report
the feasibility of this route of drug administration at relapse and as part of palliative care with
infrequent complications and prolonged symptom free intervals. Rutkowski reported very high
survival rates in pre-school children treated with chemotherapy-only strategy including
intraventricular methotrexate [109]. The proposal that intrathecal therapy be tested in a
prospective European trial of medulloblastoma in this young age group is currently the focus of
debate [139].

In order to further develop an enhanced evidence-base for the selection of drugs that are
effective against medulloblastoma, suitable for administration by the intrathecal route, and
non-toxic to the nervous system, we developed criteria for the ideal intrathecal agent.
Following this a systematic literature review was conducted using these criteria to identify
candidate drugs worthy of further trial for intrathecal use in medulloblastoma.

Method
Identification of candidate drugs
A comprehensive list of chemotherapy agents was extracted from a drug pharmacopoeia [87].
Properties of the ideal intrathecal drug were identified based upon literature review [4, 10, 13,
4
33, 53, 102, 108, 132, 136, 143, 150, 151] and grouped according to: ideal clinical
properties, ideal biological properties and ideal physico-chemical and pharmaceutical
properties.

Ideal Clinical Properties
Non-irritant
The drug would need to be non-irritant to avoid chemical arachnoiditis or meningitis. Any drug
reported in any of our reference sources to cause irritation or thrombophlebitis was therefore
eliminated from further consideration.

Neurotoxicity
Any drug given intrathecally has a significant risk of neurotoxicity. Evidence for neurotoxicity
when given systemically or intrathecally was determined as an unacceptable risk for further
evaluation of CSF administration. It was not possible to grade the neurotoxicities as they were
variably reported. Some drugs which are not usually neurotoxic when given systemically at
conventional doses, may be toxic if given intra-arterially, intrathecally or in very high doses
[130]. Any drug reported in any of our reference sources to cause neurotoxicity was therefore
eliminated from further consideration. Methotrexate and cytosine arabinoside, whilst suitable
for IT delivery, have only been studied in medulloblastoma with concurrent systemic
chemotherapy agents, the chemosensitivity of medulloblastoma to these drugs is, therefore,
unknown.

Tumour sensitivity / mechanism of action
Evidence of activity of the drug against medulloblastoma, PNET or leptomeningeal
carcinomatosis is required to warrant further investigation. A drug with a mechanism of
action effective at the CSF/leptomeningeal interface would offer a therapeutic advantage.

Methotrexate and Cytosine Arabinoside
Interestingly, the strict application of these criteria led to the exclusion of methotrexate and
cytarabine (in its standard formulation) from the list of potential candidates. We are aware
that these agents are commonly used intrathecally. The application of ideal criteria which
identifies lack of chemosensitivity data and substantial evidence of neurotoxicity led to their
rejection from our ideal list, for the purposes of this review.

Ideal Biological properties
CSF transport system
Some drugs are removed from the CSF by facilitated diffusion using carrier transport systems
such as those for organic ions, quaternary ammonium compounds, organic bases and acids,
also transporters conferring multi-drug resistance such as P-glycoprotein, multi-drug
resistance protein 1, monocarboxylic acid and organic ion transporters [126]. The ideal
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intrathecal agent will have no active transport system that is capable of removing it from the
CSF.

Cell cycle non-specific agent
Cells in the process of dissemination may be in a non-cycling, G
o
, or slow cycling phase. Drugs
which act at specific stages of the cell cycle will need to be in contact with the cells for
sufficient time for the cells to go through active cell division, to ensure an effective cell kill. An
ideal agent would therefore be cell cycle non-specific in its action.

Ideal Physicochemical and pharmaceutical properties
Active in CSF
Drugs requiring enzyme activation (e.g. cyclophosphamide) are unlikely to be active since
there are very few enzyme systems present in the CSF. Drugs administered in their active
form or with predictable activation (e.g. hydrolysis) are proposed. Those requiring other
processes of activation are excluded.

Factors affecting BBB permeability
Drugs in the CSF are likely to be in equilibrium with plasma as determined by the
characteristics of the BBB and the drugs physical characteristics. Factors that reduce a drugs
capacity to diffuse across the BBB and therefore limit drug efflux include: low lipophilicity, high
hydrophilicity, ionised state at CSF pH of 7.3 and molecular weight >700 Da [53]. Such
properties should therefore enhance sustained CSF drug levels and are therefore preferred for
intrathecal therapy.

Protein binding
Ideally drugs normally protein bound are excluded from crossing the BBB due to molecular
size, direct injection would overcome this and sustain their presence in CSF. This criteria has,
however, not been used as the information was not available for the majority of drugs.

Formulation for CSF administration
The drug must be soluble in the appropriate concentration for intrathecal administration, and
in a vehicle which is suitable for this route, including bio-compatibility with surgical delivery
systems such as ventriculostomy reservoirs.

(Insert Table 1 here - Summary of clinical, biological and physicochemical / pharmaceutical
properties used to justify selection or rejection of drugs)

Literature search strategy and selection criteria
An initial search for the properties of each drug on the candidate list was undertaken by
screening standard pharmaceutical texts [9, 30, 87] and by consulting the manufacturer.
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Some information was obtained from these sources. This permitted immediate elimination of a
number of drugs due to evidence of irritancy, neurotoxicity and the need for liver enzyme
activation. However details of ionisation state and degree of protein binding for many drugs
was unavailable despite direct approaches to manufacturers.

For the remaining drugs, Medline (1966 - present) and Embase (1980 present) searches
were performed. Each drug name was separately combined with the following terms:
medulloblastoma, PNET and leptomeningeal carcinomatosis, used in the 'exploded' form.
Where hits exceeded 50 for a combination of terms, the search was further narrowed by
combining that search with intrathecal administration. The full text of papers with relevant
abstracts were obtained and physicochemical information was extracted as well as:
evidence of the drugs activity against medulloblastoma, PNET and leptomeningeal
carcinomatosis in vitro and in vivo
absence or presence of neurotoxicity reported from systemic or intrathecal administration
documentation of intrathecal administration in vivo and in vitro.


Results
One hundred and twenty-six drugs were initially identified for investigation. 35 were
immediately rejected after consulting standard pharmaceutical texts where there was
documentation of irritant qualities, neurotoxicity or the need for enzyme activation of a pro-
drug. Literature searches for the remaining 91 drugs identified 33,627 hits. Screening of
abstracts reduced this to 200 full papers which were read, justifying the rejection of a further
64 drugs (see Table 2a & b).

(Insert Table 2 here List of chemotherapy drugs considered with selection / rejection status
and rejection justification)

Rejected drugs
Of the 126 licensed and investigational anti-cancer chemotherapy agents identified, 99 drugs
were excluded (Table 2a & b). In 45 cases rejection was due solely to the lack of information.
The remaining 54 drugs were rejected for a single reason (n=50) or a combination of two
reasons (n=4). Where a single reason is cited the justifications were: neurotoxicity (n=24),
irritant (n=15), needs activation (n=5), neurotoxic when given intrathecally (n=4), lack of
activity in relevant tumour type (n=2). Where two reasons were cited, the justifications were:
neurotoxic and irritant (n=3), and needs activation and systemic administration results in
equivalent concentration (n=1).

Prioritised drugs for intrathecal use
7
From our initial list of 126 drugs, 12 drugs have been identified as suitable for further testing
by the intrathecal route in medulloblastoma. Fifteen other potential candidates lack sufficient
information to currently justify exploration of intrathecal administration, but warrant further
research. The 27 drugs are therefore candidates for further testing via the intrathecal route
focussed upon in childhood medulloblastoma and other leptomeningeal malignancies.

The most promising 12 drugs for PNET/medulloblastoma with prior reported clinical experience
are detailed in Table 3 with justification of their potential for future research.

(Insert Table 3 here Drugs currently eligible for consideration for trial by intrathecal
administration for medulloblastoma)

Evaluation in progress
Liposomal cytarabine and mafosfamide are currently undergoing phase 2 trials by the
intrathecal route in children with brain tumours with leptomeningeal spread. Liposomal
cytarabine has now been associated with significant neurotoxicity, particularly in adult patients
also treated with systemic cytarabine [16]. It may be better tolerated in children. Comitant
systemic corticosteroid treatment is recommended. Further studies are needed to establish
optimal use of this drug.

These should be the first drugs to undergo further evaluation in phase 3 studies in order to
further evaluate their efficacy and toxicity profiles and optimise dose and administration
regimens.

Evaluation required in Phase 2 trials
Carboplatin, etoposide, spartaject, busulfan and nimustine are agents suitable for treatment of
PNET and are therefore also suitable for further investigation by the intrathecal route.
Topotecan is undergoing intrathecal phase 2 studies in children and adults with refractory
neoplastic meningitis; however chemical arachnoiditis has been reported as a dose limiting
toxicity. Etoposide and nimustine have already been tested clinically with some encouraging
results; however refinement of drug delivery systems may be necessary to prolong exposure in
order to overcome their rapid removal from the CSF, their currently observed efficacy may,
therefore, be sub-optimal.

Phase 1 studies required
Floxuridine and 4-hydroperoxycyclophosphamide have been tested intrathecally in limited
studies and have shown promise in relevant tumour types. The intrathecal use of these two
agents should also be further explored.

Pre-clinical evaluation required
8
Diaziquone is lipophilic and has low ionisation at CSF pH. Together these physical properties
suggest it may not remain in the CSF unless delivered in a sustained release formulation or as
an infusion. It is active in PNET and leptomeningeal carcinomatosis and has been used
intrathecally in human studies. Mercaptopurine has been tested by the intraventricular route
in animals and children with leptomeningeal dissemination of ALL but there is no evidence of
efficacy in primary brain tumours. Rubitecan has been shown to be safe & effective in a rat
model against human glioblastoma multiforme neoplastic meningitis.

Temozolomide is effective in medulloblastoma when given orally. A microcrystalline
preparation has been used intrathecally in animal studies justifying further study if an
appropriate formulation could be developed. Its lipophilicity would favour a sustained release
formulation or an infusion

Pre-clinical animal evaluation
The nine drugs in Table 4 have documented activity in the relevant tumour types but no
information was found on intrathecal use. These drugs would be worthy of intrathecal testing.

(Insert Table 4 here - Drugs with documented activity in the relevant tumour types but no
information on intrathecal use)

The drugs in Table 5 have been tested in studies in the relevant tumour types by the
intrathecal route (some animal, some human) with mixed reports of toxicity and efficacy. With
the exception of bleomycin where neurotoxicity seems to be a major problem, these may well
be worthy of further research. Carmustine is licensed in a sustained release preparation
designed to be implanted into tumour resection cavities as an adjunct to surgery for GBM after
relapse. However, it is documented also to have serious neurotoxicity when given systemically
and therefore has not been prioritised in the list of drugs for further study.

Gemcitabine has been tested by the intrathecal route in a patient with leptomeningeal
carcinomatosis from non small cell lung cancer and has been used intrathecally in non-human
primate models [35, 45, 67]. Based upon this, a phase 1 clinical trial of intrathecal
gemcitabine has been conducted in ten patients with neoplastic meningitis including one with
medulloblastoma. However, dose limiting neurotoxicity was observed in patients who had
previously received CNS-directed therapies [15] The authors concluded that the potential for
severe neurotoxicity precludes further development of gemcitabine for intrathecal
administration.

(Insert Table 5 here - Drugs tested by the intrathecal route (some animal, some human) with
mixed reports of toxicity and efficacy)

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Discussion
This work helps draw three important conclusions. First, many of the proposed ideal criteria,
have not been applicable because of inadequate data in the academic and commercial
information domains. A more open shared strategy between pharma and academic
researchers of basic pharmacological data is required. Secondly, using supplementary clinical
criteria, the systematic review has identified 12 drugs suitable for immediate intrathecal use in
medulloblastoma, 15 other candidate drugs were identified for further evaluation prior to
human use. Finally, the extended list of agents, identified here as suitable for intrathecal use,
justifies further efforts to explore their role as part of brain sparing strategies in clinical trials.

Ideal criteria
The pre-determined criteria were applicable in their entirety in only eight drugs resulting in the
current drug selection being based primarily upon alternative criteria including: a) clinical
evidence of tumour chemo-sensitivity, b) previously reported intrathecal use and c) reported
evidence of neurotoxicity after systemic or intrathecal administration. The overwhelming
reason for rejection was because of either insufficient or inconsistent information in the
academic domain (Table 2). It remains unclear why this basic physicochemical data is
unavailable, highlighting the importance of promoting a more open ethic between pharma and
academic groupings exploring novel applications of existing cancer drugs and in particular for
intrathecal administration. This large category of known, rejected drugs as well as a presumed
larger number of unknown candidate agents in industrial archives constitutes an untapped
resource. In contrast, drugs with inconsistent data, but promising early laboratory or clinical
evidence of suitability, are a group where further efforts for their evaluation are justified.
Furthermore, as new biological agents are developed which affect tumour behaviour via non
cytotoxic mechanisms, the lack of publication of physico-chemical criteria or clinical
pharmacological data will slow down the process of their selection or rejection for intrathecal
use.

Drug selection: From this review, 12 agents were identified as potentially suitable for human
use. The three largest previous reviews of this treatment approach do specify optimal drug
criteria for intrathecal use but do not specify the method by which they developed their
proposed drug selections for intrathecal use.

(Insert Table 6 here - Comparison of candidate intrathecal agents by previous published
reviews)

The current review has identified four additional drugs: carboplatin, floxuridine, 4-
hydroperoxycyclophosphamide and rubitecan, yet rejected cytarabine (in its standard
formulation) and methotrexate because of evidence of neurotoxicity. The extensive experience
with these two latter drugs for prophylactic, therapeutic and palliative strategies in acute
10
leukaemia and lymphoma has permitted comprehensive reporting of neurotoxicity. It has been
proposed that enhanced and prolonged drug levels due to reduced permeability of the BBB
arising from tumour involvement at sites of CSF efflux is a hypothesis for this observed effect
[23, 24, 55, 86]. Carmustine in its wafer preparation (Gliadel) is used for interstitial therapy
for GBM at relapse (ref). Prior reports of neurotoxicity after intra-arterial administration
might have excluded this drug. Its lipophilicity makes it unsuitable as an intrathecal agent
without adaptation to its formulation to slow its release or as an infusion. Its current
application within a sustained release wafer is, therefore, compatible with the ideal criteria
based upon physicochemical properties but not via the intrathecal route aimed at generalised
CSF distribution.

Nine drugs were identified with evidence of efficacy against medulloblastoma but insufficient
information about their suitability for intrathecal use (Table 4). More information about their
physicochemical / cycle specific and neurotoxicity properties is required before they could be
accepted/rejected for evaluation by the ideal criteria. The information that was missing was
physicochemical (7), cell cycle specificity (4) and neurotoxicity (7). The previous reviews [17,
49, 108] made no suggestions for this category of agents. Drugs, tested by the intrathecal
route but with mixed reports of toxicity (n=7 Table 5), were based upon clinical case reports
from both animal and human experimentation, limiting the scope of this group as a source of
new drugs for testing. There were conflicting reports of neurotoxicity. In only one drug was
there a complete physico-chemical dataset (dacarbazine). In three drugs (bleomycin, busulfan
and carmustine) drug formulation was reported to influence neurotoxicity and efficacy. This
group of drugs highlights the importance of selecting or developing drug formulations that
maximise efficacy and minimise neurotoxicity.

Having identified a short list of 12 drugs suitable for human trial via the intrathecal route
(table 3) an attempt to select those suitable for immediate use has been made based upon
currently available data. Carboplatin, etoposide and nimustine are identified as having the
strongest evidence base for intrathecal use. Liposomal cytarabine (Depocyte) and
mafosfamide are currently undergoing phase 2 trials; their efficacy and toxicity will need to be
judged when given without concomitant chemotherapy or radiotherapy. Mafosfamide is
unlicensed and is therefore unavailable for clinical use in trial or therapy (Personal
communication: Irene Slavc - irene.slavc@akh-wien.ac.at; Dr Susan Blaney:
smblaney@txccc.org). Liposomal cytarabine (Depocyte) is being extensively investigated in adult
studies in a variety of cancer types. Preliminary information has identified substantial
evidence of neurotoxicity [65, 81]. In selecting any of these drugs for use, the more fat
soluble drugs will require either a pharmaceutical formulation aimed at prolonging drug release
or the use of intrathecal infusions to sustain drug levels. Such infusional techniques are well
developed for intrathecal baclofen aimed at controlling spasticity and could be adapted for
such an application [123].
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Limitations: Our criteria for accepting or rejecting drugs were applied strictly therefore. Any
drug for which we found documentation of it being irritant or neurotoxic was rejected. It is
possible that this criteria was applied too strictly since, for example, methotrexate and
cytarabine (standard formulation) were excluded and liposomal cytarabine (Depocyte) has
been accepted but evidence of neurotoxicity is now emerging. However the objective of the
study was to identify drugs with ideal characteristics for intrathecal use.

It is difficult to interpret many studies of intrathecal chemotherapy in terms of efficacy, as in
many cases simultaneous systemic chemotherapy or radiation, or both were administered
along with intrathecal treatment making it unclear which component of therapy produced the
effect. Most patients recruited into such studies are refractory to other treatments and are
therefore undergoing such trials as a last resort. Despite this, measurable response to IT
therapy, introduced after systemic chemotherapy has proved refractory, is reported as
evidence of effect.

Drug administration: The clinical benefits of intrathecal administration need to be balanced
against the risks relating to safe prescribing, clinical governance, technical and toxicity
issues [38]. Furthermore, in contrast to leukaemia and lymphomas, primary CNS tumours
represent anatomical challenges to drug distribution linked to the presence of ventrico
peritoneal (VP) shunts, the influence of drainage of the third ventricle to basal cistern by
neuroendoscopic third ventriculostomy, distortion of CNS anatomy linked to post-resection
tumour bed, post operative incarceration of the posterior fossa and spinal blocks. Finally,
the ideal timing of intrathecal administration in relation to debulking surgery is unclear.
Such factors will clearly influence the distribution of CSF and any drug it carries. The
challenges of drug delivery to the brain have resulted in a considerable volume of research,
which may overcome some of these problems, through either local delivery approaches
[105, 140] or vascular delivery across the blood brain barrier [57, 79, 103]. However,
relatively little research has been focussed upon delivery systems for intrathecal delivery,
the main example being that of liposomal cytarabine [22]. The role of efflux inhibitors such
as valspodar in combination with intrathecal therapy in order to overcome the problems of
removal of drugs from the CSF by multi-drug resistance transporters could also be explored
[126].

The application of this method of drug administration in medulloblastoma is timely, as cure
rates with combined chemo-radiotherapy for both localised and metastatic cases are improved
(>70%, 5 year survival) in school age children. Novel biological markers are identifying
patients with favourable tumour types where further de-escalation of neuro-toxic cranial
radiotherapy by adjustments to dose/fractionation schedules or fields. The role of systemic
12
chemotherapy, whilst established in this age group, will be further examined in trials focussing
upon minimising toxicity.

In pre-school age children with favourable presentations (non-metastatic, completely resected,
desmoplastic histology) survival rates also exceed 70% in recently reported studies [54, 109]
using both low and high intensity chemotherapy schedules with or without intrathecal
methotrexate and with or without involved field radiotherapy. The interaction between
biological markers and these treatment strategies in this age group is yet to be studied [8, 58,
110]. The role of chemotherapy is, therefore, established. The potential for novel biological
agents is yet to be explored but is anticipated.

Selecting drugs for IT trial
The most effective and safe way of delivering a drug to the leptomeningeal CSF interface will
continue to be a challenge. In seeking to optimise drug delivery, drug selection is the first
step. The route and method of administration will need to be studied further i.e. the
intraventricular route, the lumbar route, by bolus and by infusion. Anatomical factors will
require consideration including the effects of tumour location, CSF circulation, including VP
shunting and post operative complications affecting the tumour bed. Once drugs have been
tested in phase 1 studies, then phase 2 studies looking for efficacy in patients with either
newly presenting or relapsed leptomeningeal disease will be necessary. Once a drug has been
assessed as effective by intermittent or infusional techniques of IT administration, then phase
3 trials to evaluate its clinical effectiveness or preparation of sustained release formulation for
intermittent IT administration would be justified. The preparatory clinical testing can only be
developed within centres with the relevant neuroscience / pharmaceutical / pharmacological
research expertise.

Conclusion
This review has extended the list of candidate agents suitable for further investigation of
intrathecal treatment of leptomeningeal medulloblastoma. It has identified the importance of
making basic physico-chemical criteria available to the academic domain by pharma and
academic research groupings in order to accelerate the development of new cancer agents. It
has highlighted the opportunity to replicate the success of CNS targeting of drug therapy in
leukaemia and lymphoma, by proposing trials of novel intrathecal chemotherapy in
medulloblastoma. It has identified the need to establish an acceptable process for selecting
new drugs for trial and a suitable trial design.

Acknowledgements:

This work has been supported by funding from the Childrens Brain Tumour Research Centre at
the University of Nottingham.
13

We would like to acknowledge the assistance of Professor Imti Choonara in the development of
strategy and review of the manuscript, Steve Barrett in the conduct of the literature searching
and Sue Franklin in the preparation of the manuscript.

(Word count 3919)

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[146] Yamashima T, Yamashita J, Shoin K (1990) Neurotoxicity of local administration of two nitrosoureas in
malignant gliomas. Neurosurgery 26: 794-800
[147] Yoshida T, Beuls E, Shimizu K, Koulousakis A, Sturm V (1992) Intrathecal chemotherapy with ACNU for
meningeal gliomatosis. British Journal of Cancer 66: 999-1004
[148] Yoshida T, Shimizu K, Koulousakis A, Sturm V (1992) Intrathecal Chemotherapy With ACNU In A
Meningeal Gliomatosis Rat Model. Journal Of Neurosurgery 77: 778-782
[149] Yoshimura J, Nishiyama K, Mori H, Takahashi H, Fujii Y (2008) Intrathecal chemotherapy for refractory
disseminated medulloblastoma. Child's Nervous System 24: 581-585
[150] Zimm S, Collins J, Curt G, O'Neill D, Poplack D (1984) Cerebrospinal fluid pharmacokinetics of
intraventricular and intravenous aziridinylbenzoquinone. Cancer Research 44: 1698-1701
[151] Zimm S, Collins J, Miser J, Chatterji D, Poplack D (1984) Cytosine arabinoside cerebrospinal fluid kinetics.
Clinical Pharmacological Therapeutics 35: 826-830

20
Table 1: Summary of ideal clinical, biological and physicochemical / pharmaceutical properties
used to justify selection or rejection of drugs.

Property Required
ClinicalNon-irritant
Neurotoxicity low or absent
Evidence of tumour sensitivity

Biological
CSF transport system absent
Cell cycle non-specific agent
Physicochemical & pharmaceutical
Active in CSF

Hydrophilic and/or ionised at CSF pH
therefore low membrane permeability (to
minimise diffusion out of CSF)
Molecular Size (700 Da)
Suitable formulation readily available
21
Table 2: List of chemotherapy drugs considered with selection / rejection status and rejection justification

Table 2a - Rejected chemotherapy agents plus justification


Irritant
No tumour
activity

No information
Requires
activation

Neurotoxic
Neurotoxic and
irritant
Neurotoxic via
IT route
Aclarubicin Carbetimer AG-337
(Noltatrexed)
Capecitabine Acivicin Altretamine Doxorubicin
Amsacrine Mitoguazone Amonafide Cyclophosphamide Asparaginase Chlorambucil Melphalan
Azathioprine Amrubicin Mitomycin Carmofur Mitozantrone
Dactinomycin Azacitidine Procarbazine Cisplatin **Fluorouracil
Daunorubicin Bendamustine Trofosfamide Cladribine
Epirubicin Bisantrene *Thiotepa Docetaxel
Idarubicin Caracemide Doxifluridine
Mustine
(Mechlorethamine)
Carboquone Fludarabine
Paclitaxel Chlorozotocin
(DCNU)
Fotemustine
Pirarubicin Chromomycin Gemcitabine
Piroxantrone Clofarabine Hydroxyurea
Plicamycin Crisnatol Ifosfamide
Streptozocin Decitabine Methotrexate
Valrubicin Echinomycin Mitotane
Zorubicin Edatrexate Oxaliplatin
Enloplatin Pentostatin
Enocitabine Sparfosic acid
Estramustine Spiromustine
Homoharringtonine Suramin
Ilmofosine Tegafur
Improsulfan Vinblastine
JM-216
(Satraplatin)
Vincristine
Lobaplatin Vindesine
Miboplatin Vinorelbine
Mitobronitol
22
Mitozolamide
Nedaplatin
Pemetrexed
Peplomycin
Pipobroman
Piritrexim
Porfiromycin
Prednimustine
Raltitrexed
Ranpirnase
Razoxane
Sebriplatin
Semustine
Sobuzoxane
Teloxantrone
Thioguanine
Tirapazamine
Treosulfan
Trimetrexate
Ubenimex

* Systemic administration delivers concentration to IT route
** Also irritant

23
Table 2b Selected drugs


1. Carboplatin Selection Table 3
2. Cytarabine Selection Table 3
3. Diaziquone Selection Table 3
4. Etoposide Selection Table 3
5. Floxuridine (FdUrd) Selection Table 3
6. 4-hydroperoxycyclophosphamide Selection Table 3
7. Mafosfamide Selection Table 3
8. Mercaptopurine Selection Table 3
9. Nimustine (ACNU) Selection Table 3
10. Temozolomide Selection Table 3
11. Topotecan Selection Table 3
12. Eflornithine Selection Table 4
13. Mitolactol (Dibromodulcitol) Selection Table 4
14. Didemnin B Selection Table 4
15. Irinotecan Selection Table 4
16. Lomustine (CCNU) Selection Table 4
17. Lonidamine Selection Table 4
18. Menogaril Selection Table 4
19. Tauromustine Selection Table 4
20. Teniposide Selection Table 4
21. Bleomycin Rejection Table 5 neurotoxic when given IT
22. Busulphan Selection Table 5
23. Carmustine (BCNU) Selection Table 5
24. Dacarbazine Selection Table 5
25. Fazarabine Selection Table 5
26. Ranimustine (MCNU) Selection Table 5
27. Zinostatin Selection Table 5



24
Table 3: Drugs graded by eligibility for trial by intrathecal administration for medulloblastoma

Legend
OWPC = octanol/water partition coefficient >0 = lipophilic; <0 = hydrophilic (different values obtained from different references)
pKa = dissociation constant. pKa <5.3 or >9.3 indicate an ionisation of >99% at CSF pH of 7.3
MW = molecular weightIV = intraventricular. IL = intralumbar. IC = intracavity/tumour. IT = intrathecal
RMM - refractory meningeal malignancy, MB = medulloblastoma, LMC = leptomeningeal carcinomatosis, LMM = leptopmeningeal meningitis, NM = neoplastic meningi tis3a
Agents under trial.
DRUG OWPC pKa MW Evidence of
medulloblastoma (MB /
PNET) chemosensitivity
Evidence of IT use. Cell cycle
phase
specificity
Comments Refs
Cytarabine
(liposomal
formulation)
-2.46 4.3 243 Evidence of MB sensitivity,
Randomised Clinical Trial in NM
had 13/18 responders with IT
liposomal v 3/17 with free
cytarabine.
Licensed in
lymphomatous
meningitis in adults.
Phase 1 trial in children
with NM established
maximum tolerated
dose and showed
benefit in 8/14 pts.
Phase 2 trial is in
development.
S phase Neurotoxic in standard
formulation. Liposomal
preparation used for IT is less
toxic and half life in CSF is
prolonged up to 40 times,
though is less in children than
adults. Dexametasone is
required to avoid
arachnoiditis.
[1, 11, 20,
27, 32, 33,
36, 37, 42,
44, 64, 66,
68-70, 73,
77, 78, 87,
95, 96, 130,
142]
Mafosfamide 0.56,-2.11 401 MB, PNET, ependymoma pts,
LMC -rabbit only
IV -non-human
primate, IV rabbit.
Phase 1 study in
patients with RMM, IV+
IL paediatric patients
showed good effect +
minimal toxicity. Phase
1 study has
determined maximum
tolerated dose in
children <3yrs with
newly diagnosed
embryonal tumours
phase 2 trial in
progress
non Cyclophosphamide derivative,
undergoes spontaneous
hydrolysis to active species
[1, 17, 21,
42, 87, 95,
96, 104, 120,
121, 128]


25
Table 3b: Agents suitable for clinical trial.
DRUG OWPC pKa MW Evidence of
medulloblastoma (MB /
PNET) chemosensitivity
Evidence of IT use. Cell cycle
phase
specificity
Comments Refs
Carboplatin -0.46 371 High grade gliomas, MB, PNET,
ependymoblastoma
IT in rats showed this
to be the least
neurotoxic of the
platins. Neurotoxicity
not seen until lethal
dose
non [39, 41,
95, 96,
100, 107,
118, 127]
Etoposide 0.6 9.7 589 MB IV -dogs, humans IV -
metastatic MB,
malignant meningitis.
Used IV in paediatric
patients with good
effect + minimal
toxicity
Late S, G2 Poor CSF distribution following
IV administration, possibly due
to rapid CSF clearance due to
lipophilicity and/or efflux by P-
glycoprotein and MDR-
associated protein 1.
Possible problem with IL route
due to concerns of drug and
preservatives causing spinal
cord damage.
[1, 40, 42,
87, 95, 96,
112, 114,
121, 126,
128, 133]
Nimustine (ACNU) 0.39
Water +
lipid
soluble
309 Pilocytic astrocytoma,
meningeal spread of MB, PNET,
glioblastoma, anaplastic
glioma.
MC - rat, dog, IV in
meningeal spread of
MB, PNET,
glioblastoma,
anaplastic glioma, A
phase1/11 study
involving IV/IL/
IT admin in 21 patients
(including children)
with refractory
disseminated MB
showed efficacy in
some patients
non When given IV, needed infusion
- bolus did not give adequate
subarachnoid spread as CSF
half-life very
short(approximately27min)

High priority for future study in
appropriate delivery system
[6, 42, 61,
63, 74-76,
83, 87, 95,
96, 98,
129, 131,
132, 146-
149]

26
Table 3c: Drugs requiring further investigation before clinical trial.

DRUG OWPC pKa MW Evidence of
medulloblastoma (MB /
PNET) chemosensitivity
Evidence of IT use. Cell cycle
phase
specificity
Comments Refs
Floxuridine (FdUrd) -1.16 7.44 246 MB, glioma LMC -animal +
humans, NM
LMC, NM by continuous
IT infusion.
Intracavitary
administration may be
useful in small volume
malignant brain
tumours
[1, 42, 87,
91-96, 144]
4-hydroperoxy-
cyclophosphamide
293 Promising phase 1 trial IT in
MB, PNET
Promising phase 1 trial
IT in MB, PNET. IV
administration in
monkeys
non [7, 52, 95,
96]

27
3d: Drugs requiring further investigation, lower priority.
DRUG OWPC pKa MW Evidence of
medulloblastoma (MB /
PNET) chemosensitivity
Evidence of IT use. Cell cycle
phase
specificity
Comments Refs
Diaziquone -0.758 low
ionisation
at
physiologic
al pH
364 9L rat brain tumour, LMC,
GBM, AA, paed brain tumours,
RMM, recurrent glioma phase
11 studies, MB xenograft in
mice
Rat, IV-non-human
primate studies,
Human patients
including children with
RMM phase 1/11
studies good
response
Low aqueous solubility has
caused formulation problems.
Drug shows high rate of
clearance from CSF
[1, 13, 14,
21, 31, 42,
43, 47, 62,
71, 78, 87,
95, 96, 115,
127, 150]
Mercaptopurine 0.01 7.77, 11.17 170 LMD of ALL IV - monkey then
children
S - phase Cleared from CSF at
0.63ml/min (bulk flow
0.4ml/min) suggesting an
additional mechanism of
elimination - possibly efflux by
MDR-associated protein 1 and
monocarboxylic acid
transporters
(25, 59, 60,
91, 105, 107)
Rubitecan 393 safe & effective in rat model
against human GBM xenograft
NM
IT safe & effective in
rat model of GBM NM
S-phase
Topotecan 0.83, -
0.3
6.35, 10.1 458 ependymoma, MB, high grade
glioma xenografts
IV non-human primate.
IV & IL to children &
adults with refractory
neoplastic meningitis.
Phase 2 study
underway.
S-phase Chemical arachnoiditis dose
limiting toxicity. Rapid
elimination from CSF. Novel
mechanism of action
[1, 10, 18-
21, 87, 95,
96, 99, 122,
137]

28
Table 3e: Drug with insufficient information to grade
DRUG OWPC pKa MW Evidence of
medulloblastoma (MB /
PNET) chemosensitivity
Evidence of IT use. Cell cycle
phase
specificity
Comments Refs
Temozolomide -0.58, -
1.32
194 CNS tumour xenografts, NM
Phase 2 studies in MB,
astrocytoma, glioma, GBM
microcrystalline prep
with increased
solubility - used IT in
rats with NM + malig
glioma sub arachnoid
xenografts
Spontaneous conversion to
active mitomycin in physiological
conditions. Highly insoluble in
aqueous solution,
microcrystalline form increased
solubility
[1, 42, 50,
87, 95-97,
111, 124]

29
Table 4: Drugs with documented activity in the relevant tumour types but no information on intrathecal use.
DRUG OWPC pKa MW Evidence of tumour
sensitivity
Previous IT
use.

Cell cycle
phase
specific
Neuro-
toxicity
Comments Refs
Didemnin B 3.173 1112 Some response seen in GBM
and progressive high grade
gliomas
Natural marine product, antiviral
and antineoplastic activity
[95, 96, 127]
Eflornithine -2.945 182 In combination with
mitoguazone, response seen
in anaplastic astrocytoma and
GBM
[95, 96, 127]
Irinotecan 0.03 (pH 1-6)
0.095 (pH9-12).
At pH7-slightly
more lipophilic
but likely to be
more hydrophilic
than lipophilic
1.07,
7.89
677 peripheral PNET,
neuroblastoma xenografts,
MB, glioma, ependymoma
xenografts. GBM,
ependymoma, MB (animal
models), some evidence of
activity in recurrent glioma
S-phase Requires metabolism by
carboxylesterase in liver & tissues
to SN-38 to provide most of its
cytotoxic activity it is not known if
this would occur in the CSF
[28, 59, 87, 95, 96,
106, 135, 138]
Lomustine (CCNU) 2.629 234 MB, glioma non Alkylating and carbamoylating
agent
[10, 42, 62, 85, 87,
95, 96, 114, 141]
Lonidamine 4.407 321 Prolongation of survival +
rate of 1 year survivors (62 v
35%) supratentorial glioma
Drowsiness,
weakness
Inhibits lactate production causing
interference with energy
metabolism of cancer cells
[87, 95, 96, 127]
Menogaril 1.066 542 High grade glioma, phase 1
and 11 trials give conflicting
results
? non Anthracycline, therefore likely to be
irritant
[42, 87, 95, 96,
127]
Mitolactol
(Dibromodulcitol)
-0.426 308 MB, PNET, ependymoma -
single agent, moderate effect
long duration of presence in CSF
with a half life of around 24 hours

[39, 42, 84, 87, 95,
96, 101, 116, 117]
Teniposide -0.03(estimated
by calculation
with low
confidence
probably higher)
10.13 657 MB in cell culture As etoposide efflux by P-glycoprotein [39, 42, 87, 89, 95,
96, 128, 134]
Tauromustine -0.299 287 AA, glioblastoma, clinical
improvement seen in 19/46
patients
? non (59, 60, 71)


30
Table 5: Drugs tested by the intrathecal route (some animal, some human) with mixed reports of toxicity and efficacy:
DRUG OWPC pKa MW Evidence of
tumour
sensitivity
Previous IT
use
IV = intra-

Cell cycle
phase
specific
Neurotoxicity Comments Refs
Bleomycin -2.57 1416 Intracerebral
administration in
rat 9L gliosarcoma.
Administered safely
in liposomes in
human cerebral
glioma.
Given IC in GBM -
safe but efficacy
doubtful.
<25% increase in
survival in LMC rat
model
phase 1 study
IC - no toxicity.
Rat, beagle,
human (phase 1
IV), depot
preparation
Cycling &
non-
cycling
cells
M & G2
phases
most
sensitive
Vascular necrosis
after IT (beagle),
death after IC
administration in
craniopharyngioma
patient
Antibiotic - binds to
DNA - strand scission
[25, 42, 78,
82, 88, 90,
95, 96, 113]
Busulphan -0.52 246 MB/Glioma/ependy
moma - mice.
Glioblastoma - rat.
MB-mice
Rat Non Confusion +
seizures - high
dose.
Irritant. Bifunctional
alkylating agent. Poorly
water soluble however
water-soluble
microcrystalline
formulation
(Spartaject) been
developed. Given IT in
rats, non-human
primates, adults with
LM disease + phase 1
trial in children with
LMD from brain
tumours
[3, 5, 26,
42, 51, 56,
87, 95, 96,
122, 130]
31
Carmustine (BCNU) 1.53 214 Intravenous
preparation
licensed in
brainstem glioma,
MB, astrocytoma,
ependyoma, and
metastatic brain
tumours.

GLIADEL Implant
licensed in high-
grade malignant
glioma and GBM.

IT - in hybrid
liposomes - rat
+ dog
Non Convulsions,
cerebral oedema in
patients with
implants. No
Adverse Drug
Reactions, non-
toxic in rat/dog in
liposomes. Acute
encephalopathy
after intracarotid
administration,
encephalomyelopat
hy - coma + death
with high dose,
neuroretinitis
Alkylating and
carbamoylating agent.
DNA alkylation followed
by protein
carbomoylation.
Causes local venous
irritation
[2, 9, 29,
42, 46, 48,
64, 71, 72,
85, 87, 95,
96, 128,
130, 136,
143]
Dacarbazine -0.24 4.42 182 Melanoma -
including primary
CNS
Rat.
3 case reports
human patients
Non Very toxic in rat.
CNS reaction in one
patient case report
Requires demethylation
for activation, though
dacarbazine itself
shows cytotoxic
activity.
Irritant-extravasation
causes tissue damage
+ severe pain
[9, 12, 34,
42, 78, 85,
87, 95-97,
145]
Fazarabine 496 Lack of activity in
phase 2 trial high
grade glioma. Solid
tumour activity +
leukaemia
xenografts.
Potentially useful
for NM from a
variety of tumours
IT + IV
(Ommaya
reservoir) in
Rhesus
monkeys
Probably
s-phase
Transient changes
in CSF profiles but
no evidence of
neurotoxicity after
IV in monkey
Cytarabine analogue.
Inhibits DNA synthesis
+ methylation.
Nucleoside metabolite,
intracellular activation
needed by
deoxycitidine kinase.
Clearance from CSF
five times higher than
CSF bulk flow rate in
monkey
[60, 95, 96,
119]
Ranimustine
(MCNU)
-1.29 328 pilocytic
astrocytoma
Longer half life
than ACNU in
dogs.
IT admin in 21
patients
(including
children) with
refractory
disseminated
MB showed
efficacy in
Non Mild histological
changes in dog
brain after IV
admin. IC admin
caused marked
brain oedema +
focal necrosis.
Paraplegia + double
incontinence in
some patients
receiving multiple
Nitrosourea [42, 74, 87,
95, 96, 98,
146, 149]
32
some. IL bolus injections
Zinostatin Glioblastoma,
astrocytoma
single case
report
No CNS toxicity
when given via
carotid artery
Antineoplastic
antibiotic.
Does not permeate
BBB in normal brain.
Half life CSF=50sec
[74, 87, 95,
96, 98, 146]


33

Table 6: Comparison of candidate intrathecal agents by previous published reviews
Fleischack [49]. Ruggiero [108]. Blaney [17] Conroy
Intracavitary
bleomycin

Carboplatin
Cytarabine Cytarabine
Liposomal cytarabine
(DepoCyte)
Liposomal cytarabine
(DepoCyte)
Liposomal cytarabine
(DepoCyte)
Liposomal cytarabine
(DepoCyte)
Diaziquone Diaziquone
Etoposide Etoposide
Floxuridine (FdUrd)
4-Hydroxyperoxy-
cyclophosphamide
Mafosfamide Mafosfamide Mafosfamide Mafosfamide
Mercaptopurine Mercaptopurine Mercaptopurine
Methotrexate Methotrexate
Monoclonal
antibodies

Nimustine (ACNU) Nimustine (ACNU)
Rubitecan
Temozolomide Temozolomide
Thiotepa
Topotecan Topotecan Topotecan
34